Signal transducer and activator of transcription 4

Definition:

Transcriptional regulator mainly expressed in hematopoietic cells that plays a critical role in cellular growth, differentiation and immune response. Plays a key role in the differentiation of T-helper 1 cells and the production of interferon-gamma. Participates also in multiple neutrophil functions including chemotaxis and production of the neutrophil extracellular traps (By similarity). After IL12 binding to its receptor IL12RB2, STAT4 interacts with the intracellular domain of IL12RB2 and becomes tyrosine phosphorylated. Phosphorylated STAT4 then homodimerizes and migrates to the nucleus where it can recognize STAT target sequences present in IL12 responsive genes. Although IL12 appears to be the predominant activating signal, STAT4 can also be phosphorylated and activated in response to IFN-gamma stimulation via JAK1 and TYK2 and in response to different interleukins including IL23, IL2 and IL35. Transcription activation of IFN-gamma gene is mediated by interaction with JUN that forms a complex that efficiently interacts with the AP-1-related sequence of the IFN-gamma promoter (By similarity). In response to IFN-alpha/beta signaling, acts as a transcriptional repressor and suppresses IL5 and IL13 mRNA expression during response to T-cell receptor (TCR) activation.

References:

[1]. B B Yao, et al. Direct interaction of STAT4 with the IL-12 receptor. Arch Biochem Biophys. 1999 Aug 1;368(1):147-55. [Content Brief]

[2]. Sarah R Gonzales-van Horn, et al. STAT4-mediated transcriptional repression of the IL5 gene in human memory Th2 cells. Eur J Immunol. 2016 Jun;46(6):1504-10. [Content Brief]

[3]. Yanan Sophia Zhang, et al. Acetylation licenses Th1 cell polarization to constrain Listeria monocytogenes infection. Cell Death Differ. 2022 Nov;29(11):2303-2315. [Content Brief]

[4]. C M Bacon, et al. Interleukin 12 induces tyrosine phosphorylation and activation of STAT4 in human lymphocytes. Proc Natl Acad Sci U S A. 1995 Aug 1;92(16):7307-11. [Content Brief]

[5]. R Visconti, et al. Importance of the MKK6/p38 pathway for interleukin-12-induced STAT4 serine phosphorylation and transcriptional activity. Blood. 2000 Sep 1;96(5):1844-52. [Content Brief]

[6]. B Oppmann, et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity. 2000 Nov;13(5):715-25. [Content Brief]

[7]. Meng Li, et al. Interleukin-35 inhibits lipopolysaccharide-induced endothelial cell activation by downregulating inflammation and apoptosis. Exp Cell Res. 2021 Oct 15;407(2):112784. [Content Brief]

[8]. S S Cho, et al. Activation of STAT4 by IL-12 and IFN-alpha: evidence for the involvement of ligand-induced tyrosine and serine phosphorylation. J Immunol. 1996 Dec 1;157(11):4781-9. [Content Brief]

[9]. Akio Morinobu, et al. STAT4 serine phosphorylation is critical for IL-12-induced IFN-gamma production but not for cell proliferation. Proc Natl Acad Sci U S A. 2002 Sep 17;99(19):12281-6. [Content Brief]

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